The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors

Abstract

Background Pharmacokinetic (PK) studies suggest that talazoparib is primarily eliminated unchanged via renal excretion. The current study investigated how varying degrees of renal impairment may affect the PK of talazoparib, and evaluated the safety and tolerability of talazoparib, in patients with advanced solid tumors with/without renal impairment. Methods Patients with advanced solid tumors and normal renal function or different degrees of renal impairment measured by estimated glomerular filtration rate (eGFR: mild = 60-89, moderate = 30-59, severe = 15-29 mL/min/1.73 m 2) were enrolled in this open-label, non-randomized, phase I study. Talazoparib was administered orally at 0.5 mg/day for 22 days. Primary PK parameters included the area under the plasma concentration-time curve from 0 to 24 h (AUC 0-24) and maximum observed plasma concentration (C max) at steady state (Day 22). Safety and tolerability were also investigated. Results Thirty-four patients were enrolled. At Day 22, compared with patients with normal renal function (n = 9), patients with mild (n = 9), moderate (n = 8), or severe (n = 8) renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC 0-24 , and a 11.1%, 31.6%, and 89.3% increase in talazoparib C max , respectively. Talazoparib was generally well tolerated, and overall there were no notable differences in the treatment-emergent adverse event profile across renal function groups. Conclusions Exposure to talazoparib increased with worsening renal impairment. Overall, this study confirms current dosing recommendations in patients with mild and moderate renal impairment (1 mg/day and 0.75 mg/day, respectively) and indicates that a lower starting dose of 0.5 mg/day should be considered for patients with severe renal impairment. Clinical Trials Registration NCT02997163.

Evaluation of pharmacokinetics and safety of talazoparib in patients with advanced cancer and varying degrees of hepatic impairment

“…If plasma protein binding is comparable across hepatic function groups, total plasma concentration will be used for PK analysis. See the Supporting Information for a description of bioanalytical methods and assay performance 10 …”

“…A previous population pharmacokinetic (PK) analysis using pooled data from four clinical studies that included 490 patients indicated that talazoparib exposure was affected by Asian race, renal impairment and concomitant administration with strong P‐glycoprotein (P‐gp) inhibitors 8 . The impact of strong P‐gp inhibitors and renal impairment was confirmed by two specific phase I studies 9,10 …”

“…8 The impact of strong P-gp inhibitors and renal impairment was confirmed by two specific phase I studies. 9,10 Hepatic impairment may affect the PK of a drug through multiple mechanisms, such as altering the metabolism, biliary secretion and protein binding of drugs, or shunting of blood past the liver. 11 Although hepatic elimination plays a much lesser role in the clearance of talazoparib than renal excretion, the potential impact of moderate or severe hepatic impairment on talazoparib PK cannot be ruled out.…”

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

“…The maximum tolerated dose of talazoparib was determined to be one mg daily, but sustained PARP inhibition was reported at dosages as low as 0.60 mg/day [ 94 , 95 ]. Talazoparib is largely eliminated by the kidneys after limited hepatic metabolization [ 96 , 97 ]. Combination trials have included carboplatin, which caused significant hematologic toxicity [ 98 ]; temozolomide [ 99 ]; and irinotecan [ 100 ].…”

“…Certain medications may inhibit or increase the serum concentration of p-glycoprotein, and screening for interactions is necessary [ 17 ]. Talazoparib undergoes minimal hepatic metabolism [ 96 , 97 ]. Renal excretion accounts for 69% of the drug clearance, and up to 54.6% of the drug is excreted unchanged in the urine [ 96 , 97 ].…”